Universität zu Köln

Salpini, Romina ORCID: 0000-0002-2488-2082, Colagrossi, Luna ORCID: 0000-0001-5618-1523, Bellocchi, Maria Concetta, Surdo, Matteo, Becker, Christina, Alteri, Claudia ORCID: 0000-0003-4270-5079, Aragri, Marianna, Ricciardi, Alessandra, Armenia, Daniele ORCID: 0000-0002-3406-7014, Pollicita, Michela, Di Santo, Fabiola, Carioti, Luca, Louzoun, Yoram, Mastroianni, Claudio Maria, Lichtner, Miriam, Paoloni, Maurizio, Esposito, Mariarosaria, D'Amore, Chiara, Marrone, Aldo, Marignani, Massimo ORCID: 0000-0002-8912-9972, Sarrecchia, Cesare, Sarmati, Loredana, Andreoni, Massimo ORCID: 0000-0002-3205-9758, Angelico, Mario, Verheyen, Jens, Perno, Carlo-Federico and Svicher, Valentina (2015). Hepatitis B Surface Antigen Genetic Elements Critical for Immune Escape Correlate With Hepatitis B Virus Reactivation Upon Immunosuppression. Hepatology, 61 (3). S. 823 - 834. HOBOKEN: WILEY-BLACKWELL. ISSN 1527-3350

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Abstract

Hepatitis B virus (HBV) reactivation during immunosuppression can lead to severe acute hepatitis, fulminant liver failure, and death. Here, we investigated hepatitis B surface antigen (HBsAg) genetic features underlying this phenomenon by analyzing 93 patients: 29 developing HBV reactivation and 64 consecutive patients with chronic HBV infection (as control). HBsAg genetic diversity was analyzed by population-based and ultradeep sequencing (UDS). Before HBV reactivation, 51.7% of patients were isolated hepatitis B core antibody (anti-HBc) positive, 31.0% inactive carriers, 6.9% anti-HBc/anti-HBs (hepatitis B surface antibody) positive, 6.9% isolated anti-HBs positive, and 3.4% had an overt HBV infection. Of HBV-reactivated patients, 51.7% were treated with rituximab, 34.5% with different chemotherapeutics, and 13.8% with corticosteroids only for inflammatory diseases. In total, 75.9% of HBV-reactivated patients (vs. 3.1% of control patients; P<0.001) carried HBsAg mutations localized in immune-active HBsAg regions. Of the 13 HBsAg mutations found in these patients, 8 of 13 (M103I-L109I-T118K-P120A-Y134H-S143L-D144E-S171F) reside in a major hydrophilic loop (target of neutralizing antibodies [Abs]); some of them are already known to hamper HBsAg recognition by humoral response. The remaining five (C48G-V96A-L175S-G185E-V190A) are localized in class I/II-restricted T-cell epitopes, suggesting a role in HBV escape from T-cell-mediated responses. By UDS, these mutations occurred in HBV-reactivated patients with a median intrapatient prevalence of 73.3% (range, 27.6%-100%) supporting their fixation in the viral population as a predominant species. In control patients carrying such mutations, their median intrapatient prevalence was 4.6% (range, 2.5%-11.3%; P<0.001). Finally, additional N-linked glycosylation (NLG) sites within the major hydrophilic loop were found in 24.1% of HBV-reactivated patients (vs. 0% of chronic patients; P<0.001); 5 of 7 patients carrying these sites remained HBsAg negative despite HBV reactivation. NLG can mask immunogenic epitopes, abrogating HBsAg recognition by Abs. Conclusion: HBV reactivation occurs in a wide variety of clinical settings requiring immune-suppressive therapy, and correlates with HBsAg mutations endowed with enhanced capability to evade immune response. This highlights the need for careful patient monitoring in all immunosuppressive settings at reactivation risk and of establishing a prompt therapy to prevent HBV-related clinical complications. (Hepatology 2015;61:823-833)

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Salpini, Romina UNSPECIFIED orcid.org/0000-0002-2488-2082 UNSPECIFIED Colagrossi, Luna UNSPECIFIED orcid.org/0000-0001-5618-1523 UNSPECIFIED Bellocchi, Maria Concetta UNSPECIFIED UNSPECIFIED UNSPECIFIED Surdo, Matteo UNSPECIFIED UNSPECIFIED UNSPECIFIED Becker, Christina UNSPECIFIED UNSPECIFIED UNSPECIFIED Alteri, Claudia UNSPECIFIED orcid.org/0000-0003-4270-5079 UNSPECIFIED Aragri, Marianna UNSPECIFIED UNSPECIFIED UNSPECIFIED Ricciardi, Alessandra UNSPECIFIED UNSPECIFIED UNSPECIFIED Armenia, Daniele UNSPECIFIED orcid.org/0000-0002-3406-7014 UNSPECIFIED Pollicita, Michela UNSPECIFIED UNSPECIFIED UNSPECIFIED Di Santo, Fabiola UNSPECIFIED UNSPECIFIED UNSPECIFIED Carioti, Luca UNSPECIFIED UNSPECIFIED UNSPECIFIED Louzoun, Yoram UNSPECIFIED UNSPECIFIED UNSPECIFIED Mastroianni, Claudio Maria UNSPECIFIED UNSPECIFIED UNSPECIFIED Lichtner, Miriam UNSPECIFIED UNSPECIFIED UNSPECIFIED Paoloni, Maurizio UNSPECIFIED UNSPECIFIED UNSPECIFIED Esposito, Mariarosaria UNSPECIFIED UNSPECIFIED UNSPECIFIED D'Amore, Chiara UNSPECIFIED UNSPECIFIED UNSPECIFIED Marrone, Aldo UNSPECIFIED UNSPECIFIED UNSPECIFIED Marignani, Massimo UNSPECIFIED orcid.org/0000-0002-8912-9972 UNSPECIFIED Sarrecchia, Cesare UNSPECIFIED UNSPECIFIED UNSPECIFIED Sarmati, Loredana UNSPECIFIED UNSPECIFIED UNSPECIFIED Andreoni, Massimo UNSPECIFIED orcid.org/0000-0002-3205-9758 UNSPECIFIED Angelico, Mario UNSPECIFIED UNSPECIFIED UNSPECIFIED Verheyen, Jens UNSPECIFIED UNSPECIFIED UNSPECIFIED Perno, Carlo-Federico UNSPECIFIED UNSPECIFIED UNSPECIFIED Svicher, Valentina UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-411179
DOI:	10.1002/hep.27604
Journal or Publication Title:	Hepatology
Volume:	61
Number:	3
Page Range:	S. 823 - 834
Date:	2015
Publisher:	WILEY-BLACKWELL
Place of Publication:	HOBOKEN
ISSN:	1527-3350
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language MAJOR HYDROPHILIC REGION; NUCLEOS(T)IDE ANALOGS; CHEMOTHERAPY; LAMIVUDINE; LYMPHOMA; THERAPY; HBSAG; TRANSPLANTATION; PROPHYLAXIS; MUTATIONS Multiple languages Gastroenterology & Hepatology Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/41117